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Abstract
Hepatitis E was identified as an epidemic of non-A,
non-B hepatitis from Kashmir, India in 1978. Hepatitis E
virus (HEV), the etiological agent is the sole member of
family Hepeviridae. The virus has marked heterogeneity
and infects many animals like bats, camel, chicken, deer,
boar, mongoose, pigs, rats, rabbit and cutthroat trout.
Hepatitis E is a disease with a major global impact and
has two distinct epidemiological patterns. Hepatitis E
is an imperative health issue in developing nations,
transmitted through sullied water and happens most
every now in young adults. The disease is particularly
severe during pregnancy and in people with underlying
liver cirrhosis. Autochthonous hepatitis E is increasingly
recognized in developed countries. The virus infects
dome st ic pigs , wild bo ar and Si ka deer i n these
countries. HEV infections in humans occur by eating the
undercooked game flesh, raw liver from supermarkets
and Figatelli sausages. Blood transfusion-associated
HEV infections occur in many countries and screening
of donors for HEV RNA is under consideration. Hepatitis
E causes a number of extrahepatic diseases, including
a wide spectrum of neurological syndromes. HEV
genotype 3 causes prolonged viremia, chronic hepatitis,
liver fibrosis and cirrhosis in organ transplant patients.
The virus is amenable to ribavirin monotherapy and
most patients clear the virus in a few weeks. Hepatitis
E vaccine -239, marketed in China, has shown high
efficacy with sustained protection for over four years.
Key words: Communicable diseases; Discovery; Hepatitis
E; Hepatitis E virus; Vaccine; Zoonosis
© The Author(s) 2016. Published by Baishideng Publishing
Group Inc. All rights reserved.
Core tip: Discovery of hepatitis E came to lime
light when 1978-Kashmir epidemic of hepatitis was
investigated. Hepatitis E is being recognized as a clinical
entity of reemerging importance. Hepatitis E virus has
marked heterogeneity and infects many animals like
Hepatitis E: Discovery, global impact, control and cure
Mohammad S Khuroo, Mehnaaz S Khuroo, Naira S Khuroo
Mohammad S Khuroo, Naira S Khuroo, Digestive Diseases
Centre, Dr. Khuroo’s medical Clinic, Srinagar, Kashmir 190010,
India
Mohammad S Khuroo, Sher-I-Kashmir Institute of Medical
Sciences, Srinagar, Kashmir 190010, India
Mehnaaz S Khuroo, Department of Pathology, Govt. Medical
College, Srinagar, Kashmir 190001, India
Author contributions: All three authors contributed equally;
Khuroo Mehnaaz S and Khuroo NS conducted the literature
search; Khuroo Mohammad S wrote the paper; all authors read
the paper and made necessary corrections.
Conflict-of-interest statement: The authors report no conflict
of interest.
Open-Access: This article is an open-access article which was
selected by an in-house editor and fully peer-reviewed by external
reviewers. It is distributed in accordance with the Creative
Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this
work non-commercially, and license their derivative works on
different terms, provided the original work is properly cited and
the use is non-commercial. See: http://creativecommons.org/
licenses/by-nc/4.0/
Manuscript source: Invited manuscript
Correspondence to: Mohammad S Khuroo , Director,
Digestive Diseases Centre, Dr. Khuroo’s medical Clinic, Sector 1,
SK Colony, Qamarwari, Srinagar, Kashmir 190010,
India. khuroo@yahoo.com
Telephone: +91-194-2492398
Fax: +91-194-2491190
Received: March 26, 2016
Peer-review started: March 26, 2016
First decision: May 12, 2016
Revised: June 10, 2016
Accepted: July 6, 2016
Article in press: July 6, 2016
Published online: August 21, 2016
REVIEW
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DOI: 10.3748/wjg.v22.i31.7030
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World J Gastroenterol 2016 August 21; 22(31): 7030-7045
ISSN 1007-9327 (print) ISSN 2219-2840 (online)
© 2016 Baishideng Publishing Group Inc. All rights reserved.
bats, camel, chicken, deer, boar, mongoose, pigs,
rats, rabbit and cutthroat trout. Originally reported as
a major health problem in poor-resource countries,
hepatitis E is now recognized as an important clinical
problem in the developed world. Zoonotic foodborne
transmission of hepatitis E virus infections has relevance
in solid organ transplant population. Major advances
have been made in managing chronic hepatitis E.
Hepatitis E causes a number of extrahepatic diseases,
including a wide spectrum of neurological syndromes.
Hepatitis E vaccine -239, marketed in China, has shown
high efficacy with sustained protection for over four
years.
Khuroo MS, Khuroo MS, Khuroo NS. Hepatitis E: Discovery,
global impact, control and cure. World J Gastroenterol 2016;
22(31): 7030-7045 Available from: URL: http://www.wjgnet.
com/1007-9327/full/v22/i31/7030.htm DOI: http://dx.doi.
org/10.3748/wjg.v22.i31.7030
INTRODUCTION
Hepatitis E was identified as an epidemic of non-A,
non-B hepatitis (NANBH) from Kashmir, India in
1978[1]. In the last 36 years since the discovery of the
disease, major advances have occurred in relation to its
causative agent, the host range in the animal kingdom,
epidemiology and modes of spread[2]. Hepatitis E virus
(HEV) infections are ubiquitous in developing countries
as a cause of epidemic and endemic acute hepatitis[3].
However, the disease is now encountered in developed
countries as well[4]. Zoonotic foodborne transmission of
HEV infection has a particular relevance to the organ
transplant population[5]. HEV infections cause a number
of non-hepatic manifestations, which include a wide
spectrum of neurological syndromes[6,7]. Transfusion-
associated HEV infections are reported with increasing
frequencies and screening of donors for HEV RNA
is being considered[8-10]. Major advances have been
made in understanding chronic hepatitis E[11] and the
commercial availability of hepatitis E vaccine (HEV-239)
in China promises control of epidemic and sporadic
hepatitis E[12]. This article shall review the knowledge
about the discovery, global impact, control and cure of
hepatitis E.
DISCOVERY
Discovery of hepatitis E came to lime light when
1978-Kashmir epidemic of hepatitis was investigated[1].
This region where the disease occurred did suffer very
hard weather conditions, lacked basic health care
delivery system and the region was devoid of high
tech cutting edge investigative facilities. Events leading
to the discovery unravel a remarkable story of human
interest, with its complexities, missteps, successes
and failures (www.drkhuroo.in)[13]. In November
1978, Dr. Mohammad S Khuroo investigated an
epidemic of jaundice in and around a town 50 km
from Srinagar, Kashmir, India. The epidemic had hit
two hundred villages with a population of 600000,
caused around 52000 patients with icteric disease and
1700 fatalities[3]. Pregnant women were more affected
and many had been reported dead. An ingenious
house-to-house investigation of this and subsequent
epidemics and sporadic disease was performed over
a 14-year period. This led us to the discovery of an
enterically transmitted NANBH, which had triggered
repeated epidemics in Kashmir[2,14]. The disease
affected young adults within the age group of 15 to 45
years. One remarkable discovery during this study was
the relationship of this disease with pregnancy[15-17].
The agent was transmitted vertically with high fetal
and perinatal mortality[18,19]. The disease was a self-
limiting and did not cause chronic viremia, chronic
hepatitis and cirrhosis[20]. The loss of IgG antibodies
occurred in over half of the population in a period of
over 14 years[21]. It was postulated that the disease
was caused by yet unrecognized human hepatitis
virus[1]. Simultaneously, a sporadic disease identical in
epidemiology and clinical features to epidemic disease
and causing around half of acute hepatitis in the
population was recognized[16,22].
An outbreak of NANBH was reported in Russian
military personal posted in Afghanistan[23]. The
epidemic had similar epidemiological features as
seen in the 1978-Kashmir epidemic. Dr. Mikhail S
Balayan, in a self-experimentation, ingested pooled
stool extracts from 9 such patients[23]. On 36th d after
ingestion of the stool extracts, he developed severe
acute hepatitis with jaundice and elevated liver tests.
Stool samples of 28th d, 43th d and 45th d showed virus-
like-particles (VLP) on immune electron microscopy. A
number of primates were experimentally infected with
the putative agent and the physicochemical properties
of the agent were studied[24].
The virus could not be cloned for a number of years
due to low yield of VLP in the infectious material. This
was overcome by the basic perception that expansive
amounts of VLP’s were gotten from bile collected from
infected primates. A partial cloning of the virus was
done by Reyes et al[25] (1990). Subsequent to this,
Tam et al[26] (1991) sequenced the full-length HEV
genome of 7.2 kb and a diagnostic assay based on
enzyme immunoassay was established.
HEV
Taxonomy and classication
HEV was originally thought to resemble HAV and
included in Picornaviridae family[27]. Once morpho-
logical features and genome organization of HEV
were available, it is surmised that HEV is similar to
noroviruses and placed in family Caliciviridae, under
hepevirus genus. Before long it was built up that HEV
has a signicant sequence difference from caliciviruses
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and was removed from Caliciviridae and included in
the “Hepatitis E-like viruses”[28]. Subsequently, based
on molecular analysis, all 4 recognized genotypes
HEV-1 to HEV-4 were classied as sole agents of genus
Hepevirus in the Hepeviridae family[29]. Avian HEV was
included in the unassigned genus. This classification
received a setback as a number of HEV closely related
to human HEV infecting rabbit and wild boar and
those more divergent HEV infecting rats, ferrets, bats
and cutthroat trout were identified. Recently, based
on phylogenetical features and HEV hosts, the ICTV
Hepeviridae study group gave a new classification
for the family Hepeviridae[30,31]. All HEV’s have been
placed under Hepeviridae family and further classied
under 2 genera namely Orthohepevirus, which included
isolates from mammals and chicken and Piscihepevirus
which included Cutthroat trout isolates. Orthohepevirus
includes species A, B, C and D, while Piscihepevirus
include species A only. Orthohepevirus A species
included isolates from man, pigs, wild boar, rabbit,
deer, mongoose and camel. This species encompassed
several HEV genotypes infecting man alone (genotype
HEV-1 and HEV-2); pigs and humans (genotype HEV-3
and HEV-4), wild boar (genotype HEV-5 and HEV-6)
and dromedaries (genotype HEV-7). Orthohepevirus
B contain viruses found in chickens and includes all
three genotypes: avian HEV-1 (isolates from chicken
in Australia), avian HEV-2 (isolates from chicken in
United States and Canada) and avian HEV-3 (isolates
from chicken in Europe and China). Orthohepevirus C
includes 2 sequences namely HEV-C1 infecting rats and
HEV-C2 infecting ferrets. Orthohepevirus D includes
a single sequence infecting bat. Recently, partial
sequences of other potential members of Hepeviridae
family have been described[32-34]. The moose virus
has been assigned to Orthohepevirus A, mink HEV to
HEV-C2 and rat HEV to HEV-C1. All known cutthroat
trout virus isolates have been included in Piscihepevirus
A species within the genus Piscihepevirus. As sequences
studied from the vast majority of the cutthroat trout
infection isolates are just 262 nucleotides long, there
are insufcient data as of now to portray outline criteria
for species inside this genus.
Physico-chemical properties
The virion is a naked particle, spherical in shape and
has icosahedral symmetry. The virus shows surface
spikes and indentations. The particle has diameter
of 27-30 nm on immune electron microscopy, 32-34
nm after sucrose gradient centrifugation and 38.5-42
nm on cryo-EM analysis[23,35]. Buoyant density of the
particles in cesium chloride is around 1.35 g/cm3[36].
The virus is relatively stable in acid and mild alkaline
conditions and unaffected by chloroform and ether
treatment. HEV-infected pig liver homogenates
maintain infectivity if incubated at 56° for 1 h,
however boiling or frying for 5 min completely
inactivates the virus. Treatment of liver suspensions
with Tween-20 (0.05%) and formalin (0.05%) reduced
infectivity by 1000-fold. HEV is susceptible to chlorine
disinfection and chlorine disinfection of water supplies
is recommended during epidemics of disease[37-39].
GENETIC ORGANIZATION
HEV genome consists of single-stranded RNA, has a
molecular weight of approximately 7.2 kb with positive-
sense polarity and is capped with 7-methylguanine
at its 5’-end and poly (A) at its 3’-end (Figure 1).
The genome has UTR’s at the 5’ end (27 nucleotides)
and at the 3’ end (65 nucleotides) and a conserved
stretch (58-nucleotides) near its 5’ end region within
open reading frame 1 (ORF1), which fold in to stem-
loop and hairpin structures. HEV RNA replicates in to a
genomic RNA of 7.2 kb and a bicistronic subgenomic
RNA of 2.2 kb. There are 3 ORFs in the genome
namely ORF1, ORF2 and ORF3[40,41].
ORF1 of the well-characterized Burmese strain
begins after 27 nucleotides of the 5’ end and extends
across the 58 nucleotides of the conserved region for
5079 nucleotides before terminating at nucleotide
position 5109[42]. ORF1 translates in to a non-structural
protein (pORF1) having 1693 amino acids (aa).
ORF1 domains along with their aa boundaries based
on Burmese isolate are methyltransferase from aa
56-240, a Y domain from aa 216-442, papain-like
cysteine protease from aa 433-592, a proline-rich
hinge domain V from aa 712-778, a X macrodomain
from aa 785-942, an RNA helicase from aa 960-1204
and RNA-dependent RNA polymerase from aa
1207-1693. HEV methyltransferase catalyzes the
capping of viral RNA. HEV papain till now has not been
associated with any functional activity of the virus.
ORF1 contains a functional protease, which may be
involved in the polyprotein processing. HEV helicase
and RNA-dependent RNA polymerase are needed
to replicate the genomic RNA. Recombinant HEV
polymerase bind to the genomic RNA at 3’ end. The
virion binding is facilitated by stem-loop structures and
poly (A) stretch.
ORF2 starts at nucleotide 5147 (38 nucleotides
3’ at the end of ORF1) and develops roughly 1980
nucleotides till nucleotide 7127[43]. ORF2 encodes
pORF2, a polyprotein of 660 amino acids, which
is involved in the virus assembly and binding and
eliciting immune response to produce neutralizing
antibodies. The pORF2 has three glycosylation sites at
137, 310 and 562 conserved asparaginase residues.
HEV full-length and truncated ORF2 gene expression
in baculovirus vectors generate capsid proteins with
different molecular weights. Of these, two HEV capsid
proteins (VLP/T=1 and VLP-T=3) form virus-like
particles (VLP). While VLP/T=1 show no encapsulated
RNA, VLP/T=3 contained about 2-kb RNA derived from
the ORF2 gene. The buoyant densities of VLP/T=1
and VLP/T=3 are 1.285 g/cm3 and 1.31 g/cm3 in CsCl
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HEV REPLICATION
HEV lacks both a proper in vitro culture system and
animal model[45] and the life cycle of HEV remains
poorly studied (Figure 2). It is assumed that HEV
reaches the host through gut epithelial cells; attach
to the surface of hepatocytes through heparin
sulfate proteoglycans, binds to a receptor and enter
the hepatocytes[46]. Once internalized, the virus is
uncoated, releases RNA and nonstructural proteins
of the virus are translated. Positive sense viral RNA is
replicated in to negative sense RNA with help of RNA-
dependent RNA polymerase. Negative sense RNA
become templates for 7.2 kb positive-sense RNA and
2.2 kb subgenocmic RNA. Subsequent to this, pORF2
and pORF3 are formed with the help of subgenocmic
RNA as template. pORF2 protein along with genomic
RNA assemble into the new virion while the pORF3
optimizes viral replication. The virion egressed from
hepatocytes are coated with pORF3 and lipid layer.
Both pORF3 and lipid layer are separated from virion
after egress from hepatocytes[47].
gradient, respectively, both smaller than the buoyant
density of native HEV particles. ORF2 expression in
Escherichia coli (E. coli) leads to the formation of
three HEV capsid proteins, which are homodimers and
include dominant antigenic sites of HEV. HEV p239
self-assemble to empty virus-like particle of 23 nm.
Baculovirus/ and E. coli expressed VLP’s are strongly
immunogenic and resemble the native virus in their
three-dimensional structure. Two VLP’s namely p239
and recombinant Sar 56 kDa have been successfully
tried as HEV vaccines. The p239 vaccine is marketed
in China as Hecolin[12].
ORF3 is 345 nucleotides in length, begins 23
nucleotides 3’ of the termination of ORF1[40,41]. ORF3
begins after nucleotide 5133 and terminates at nu-
cleotide 5477 and translates in to a phosphoprotein
(pORF3) of 114 aa. It has been suggested that pORF3
associates with the cytoskeleton and more specically
with microtubules. It is also implicated in HEV egress
from hepatocytes[44]. ORF3 overlaps ORF2 by 328
nucleotides at the 3’ end but does not overlap with
ORF1.
Genome
RNAs
ORFs
HEV proteins
27nt 58nt (conserved)
m7G-cap 5' UTR
m7G-cap
7.2 kb JR
CRE
7.2 kb (genomic)
ORF1
Cap
28
5' NCR
CRE
3' UTR
65nt
Poly (A) tail
AAAAAAAAAAAAAAAA
AAAAAAAAAAAAAAAA
2.2 kb (bicistronic subgenomic)
m7G-cap
5133 5477
ORF2
ORF3
A(n)
3' NCR
7129
51475109
pORF1
56 240 433 592 712 778 960 1204 1207 1693
MeT Y PCP V X Hel RdRp
(Macro)
216 442 785 942
pORF2
Domain 1 Domain 2 Domain 3
RNA-binding Core structural Exposed: neutralization epitope
456 607
+ + + +
Glycosylation sites: Asn137 Asn310 Asn562
C
N
NC
7 23 28 53 66 77 95 111
D1 D2 P1 P2
ALGLFCCCSSCFCLCCP PSPPMSPLRPGL RPSAP PLPHVVDLPQLG
SH3 binding and viral
egress
Phosphorylation by
MARK at Ser71
Cytoskeleton and
MKP binding
Hemopexin
binding
pORF3
SS 660
1
1114
MeT Y Pro v X Hel RdRp
Figure 1 Hepatitis E virus. Genomic organization. A: The hepatitis E virus genome; B: Genomic RNA and bicistronic subgenomic RNA; C: Open reading frames
(ORFs) and (D) 3 encoded proteins (pORF1, pORF2 and pORF3). For details, see text about hepatitis E virus. Adopted from Khuroo et al[143], 2016.
A
B
C
D
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HEV EVOLUTION
Hepatitis E is an ancient ailment. Epidemics of jaundice
have been mentioned in medieval writing and in
writings generated around 19th century. Till late it
was surmised that these epidemics were caused by
hepatitis A. Now we know that the disease in reality
closely resembled hepatitis E[48]. However, these have
not been tested serologically because of non-availability
of sera. The most recent epidemic confirmed to be
caused by HEV, though retrospectively, was the Delhi
epidemic 1955-1956[49]. Recently, the HEV evolutionary
history was studied (Figure 3)[50]. It was estimated
that the tMRCAs (times-to the most-recent-common-
ancestors) for mammalian HEV existed 536 to 1344
years ago. This progenitor develops in to two variants
namely anthropotropic varaints, evloving in to HEV-1
and HEV-2 and enzootic variants evolving in to HEV-3
and HEV-4 respectively. The anthropotropic variant is
around 367-656 years old and enzootic variant around
417 -656 years old. HEV genotypes existed at various
periods namely HEV-1 (87-199 years), HEV-3 (256-342
years) and HEV-4 (131-266 years). HEV from chicken
had existed for long in the evolutionary history.
ANIMAL RESERVOIRS
HEV was identified from pigs in the Unites States
in 1997[51] and presently known to exist in all the
countries of the world[52,53]. HEV infection develops
very early and is ubiquitous in pigs from commercial
farms. The infection is clinically silent, however,
animals do show microscopic evidence of hepatitis.
Pigs are infected by either genotype HEV-3 or HEV-4.
Both have zoonotic potential and infect humans.
HEV-3 has been detected in wild boar from Japan and
many European countries[54-56]. HEV prevalence in wild
boar was between 12.0% to 42.7% (Ig anti-HEV) and
2.5% to 25% (HEV RNA). HEV-4 and two new HEV
genotypes HEV-5 and HEV-6 have been recovered
from wild boar. HEV-3 has also been found in the sika/
Yezo deer (Cervus nippon) from Japan and red deer
(Cervus elaphus) from the Netherlands[57-59]. Mongoose
has been observed to be infected with HEV and the
full-length genomic arrangement of these confines
have been shown to assemble with genotype HEV-3.
HEV strains have been identied from rabbits from the
United States and China[60,61], included as a distinct
isolate of genotype HEV-3 and may be zoonotic. HEV
has been discovered from dromedaries from the Middle
East and the virus is named DcHEV[33]. About 1.5% of
the adult dromedary fecal samples showed presence of
DcHEV RNA. A comparative genomic and phylogenetic
analyses showed that DcHEV represents a previously
unrecognized HEV genotype and designated as HEV-7.
Recently, the zoonotic potential of DcHEV has been
confirmed in a liver transplant patient from Middle
East, who often eat camel meat and drank camel
milk[62]. Thus camel-derived food products may be
a risk factor for post-transplant hepatitis E. Avian
HEV causing BLSD (big liver and spleen disease)
was identified in Australia in 1999[63]. Subsequently,
avian HEV was identified from chicken in the United
States and Canada with HSS (hepatitis-splenomegaly
syndrome)[64]. Avian HEV shares approximately 50% to
60% nucleotide sequences with HEV from human and
Binding Virions Progeny virions
2. Entry
3. Uncoating
4
RNA
5
pORF1
pORF2
pORF3
8
2.2 kb
9
7
7.2 kb
ER
Golgi
10
11
12
Nucleus
Figure 2 Proposed replication of hepatitis E virus. For details, see text about hepatitis E replication. Adopted from Khuroo et al[143], 2016.
7.2 kb (positive-sense genomic viral RNA)
7.2 kb (negative-sense genomic viral RNA)
1
6
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pigs. At present, avian HEV has three isolates namely
from the United States, Europe and Australia[53]. HEV
infects rats (Rattus norvegicus, Rattus rattus and
Sigmodon hispidus) and bandicoots[65,66]. The rat HEV
belongs to a separate species under Orthohepevirus
C. Ferrets from a number of countries are infected
with the virus[67] and shared 72.3% identity with
rodent HEV. The ferret HEV genome organization was
found to be slightly different from other HEVs and
included a putative ORF (ORF4) of 552 nucleotides
that overlapped with ORF1. HEV has been detected in
bats from Africa, Central America, and Europe[68] and
constitute a distinct genus. HEV from cutthroat trout
(CTV) has sequence identity of 13% to 27% to human
HEV and are classified in genus Piscihepevirus and
species Piscihepevirus A in the Hepeviridae family[34].
GLOBAL DISTRIBUTION
Hepatitis E epidemiology is divided in to four distinct
zones (Figures 4 and 5).
Hyperendemic zone
Hepatitis E is hyperendemic in many countries located
in southern Asia (India, Bangladesh, Bhutan, Nepal,
Pakistan and Sri Lanka) , southeast Asia (Burma,
Cambodia, Indonesia, Thailand, Vietnam and Laos),
central Asia (Kazakhstan, Tajikistan and Uzbekistan);
north Africa (Algeria, Morocco, Sudan and Tunisia),
east Africa (Kenya, Uganda and Burundi), west Africa
(Ivory Coast, Liberia, Nigeria and Mali) and some
countries in North America (Mexico)[2]. In these
countries, HEV infections present as epidemic and
endemic disease. Hyperendemic disease is generally
brought about by HEV-1. Be that as it may, the disease
is brought on by HEV-2 in Mexico and some African
countries.
Endemic zone
Hepatitis E is endemic in many countries of Middle
East (Turkey, Saudi Arabia, Yemen, Libya, Oman,
Bahrain, Iran, Kuwait and the United Arab Emeritus),
some regions of Southeast Asia (Singapore) and South
America (Brazil, Argentina, Ecuador and Uruguay).
Hepatitis E is responsible for more than one-fourth
of all cases of acute sporadic hepatitis and fulminant
hepatitis. However, epidemics of jaundice caused by
HEV infections do not occur in these countries[69].
Distinctive pattern zone
Hepatitis E epidemiology in Egypt is distinctive and
different from other regions of the World[70,71]. Disease
occurs at young age and seroprevalence in this
community resembles that of HAV. HEV infection in
pregnant ladies is either asymptomatic or present
as mild disease. HEV infecting Egyptian population is
genotype HEV-1, with subtypes not seen in the Asian
population.
Avian
hepevirus
Rat
hepevirus
Hepevirus
ancestor
Birds/
mammals
hepevirus
ancestor
Mammals
hepevirus
ancestor Human/
swine
hepevirus
ancestor
HEV-3
HEV-4
HEV-1
HEV-2
G3/4
hepevirus
of animal
origin and
zoonotic
Human/wild boar/
swine/cervids/
rabbit/yak
Human
Rat
Avian
Current infection
Present Time line (yr)
Trout, camel, bat
ferret, moose,
wild boar
[-1344-536]
-70.000
-106
Bat
HEV
Wild boar
HEV
specific
strains
Fish
HEV
Ferret
HEV
Moose
HEV
related
virus
Camel
HEV
Figure 3 Evolutionary history of hepatitis E virus. The times to the most recent common ancestors (tMRCAs) for all four genotypes of HEV were calculated using
BEAST to conduct a Bayesian analysis of HEV. The population dynamics for genotypes 1, 3 and 4 were analyzed using skyline plots. For details see text on HEV
evolution. Source of data Purdy et al[50] 2010. HEV: Hepatitis E virus.
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Sporadic zone
Autochthonous hepatitis E is increasingly being
recognized in developed countries[72]. These infections
are caused by HEV-3 and HEV-4[73-77]. Around 50 to
100 cases of hepatitis E are reported each from France,
Germany, UK and many other European countries per
year. Seroprevalence data show that these reported
numbers are grossly lower than the actual disease
load. Most HEV infections are unrecognized as these
may not be tested or may be asymptomatic or
Figure 4 Global distribution of hepatitis E disease. See text under “global distribution” for explanation.
Hyperendemic Endemic Distinctive Sporadic
Figure 5 Global distribution of hepatitis E virus genotypes. See text under “global distribution” for explanation.
HEV-1 HEV-2 HEV-3 HEV-4
Genotypes
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misdiagnosed as drug-induced liver injury (DILI)[78,79].
Disease spectrum
Hepatitis E is a major global health problem and has
infected one-third of the world population. Hepatitis
E is a puzzling double-faced disease, with contrasting
epidemiological and disease patterns in developing and
industrialized countries (Table 1)[80,81].
Developing countries
In 2005, HEV-1 and HEV-2 worldwide disease burden
were computed in 9 of the 21 GBD regions of 2010,
representing 71% world population. It was estimated
that 20 million incident infections, 3.4 million cases,
70000 deaths and 3000 stillbirths had occurred in
2005[82]. Several factors need to be considered while
evaluating these numbers. Hepatitis E causes repeated
epidemics. The disease frequency in these regions is in
the range of 6%. The HEV antibodies show a dynamic
response, with the loss of antibodies after some time
in a sizeable proportion of the population. Recently, the
HEV reinfections with altered immune response have
been reported[14,21,83]. Thus, these calculated numbers
may grossly underestimate the disease load in such
countries.
Hepatitis E in resource poor countries causes
massive epidemics of jaundice[2,3,84]. These regions
have poor socio-economic conditions with drinking
water sources which are polluted from sewage[85].
HEV infections cause a huge number of cases and
is the reason for significant number of deaths, and
represents a health issue in endemic regions. Of
major concern is the occurrence of these epidemics
on repeated occasions[2]. Over a 4-year period
(1978-1982), four epidemics of hepatitis E were
encountered in Kashmir, India[3]. The disease affected
52000 people and caused 1700 fatalities. Hepatitis
E constitutes around 30% to 70% of sporadic viral
hepatitis in endemic areas[16,22]. The disease incidence
has been calculated to be around 45/1000 person
per year[83] and infects around 2.2 million people per
year in India[2]. HEV-related fulminant hepatic failure
is a frequent occurrence and constitutes around 43%
of all cases of fulminant hepatic failure[17,86]. The
mortality in HEV-related liver failure has been reported
as 51.9%. One of the most distinctive features
of the epidemic and endemic hepatitis E is higher
occurrence and mortality of disease in pregnancy[15,16].
Thus, the disease incidence was 8 times higher and
acute liver failure occurred 13 times more often in
pregnant women than age-matched men and non-
pregnant women. The acute liver failure occurred in
44.4% in late pregnancy. Acute liver failure during
pregnancy has limited pre-encephalopathy interval,
rapid progression, high occurrence of brain edema
and coning of the cerebellar tonsils. However, frequent
occurrence of disseminated intravascular coagulation
(DIC) was distinct feature of this disease. Considering
the association of DIC with HEV in pregnant women,
it resembles a “Schwartzman-like Phenomenon”.
HEV in pregnant women causes substantial fetal and
perinatal mortality. There are several studies reporting
intrauterine transmission of HEV with high fetal and
perinatal mortality[18,19,87]. HEV infection in cirrhotic
patients causes rapid deterioration of liver functions
and results in high mortality[88-90]. It is estimated that
around 21% of cirrhotic patients in India contract HEV
superinfection, develop rapidly progressive liver failure,
Table 1 Hepatitis E: Global epidemiology and clinical prole
Developing countries Developed countries
Genotypes HEV-1 HEV-2 HEV-3 HEV-4
Distribution Asia, Africa, Latin America Mexico, West Africa Worldwide China, East Asia,
Central Europe
Disease pattern Epidemic, Endemic Autochthonous, sporadic, case-clusters
Attack rate About 1 in 2 67%-98% asymptomatic
Seasonality Yes No
Reservoir Human Animals (pig, boar, deer)
Transmission Water, person-to-person, vertical Zoonotic-food-borne, vocational, infected water
Transfusion-associated Reported Yes (well-studied)
Seroprevalence Low (< 15 yr), rapid increase Steady increase throughout age groups; varies 7% to 21%
(15-30 yr), plateau at 30%-40%
Seroincidence 64/1000-yr 30 (South France), 2 (United Kingdom)
7 (United States)/1000-yr
Age (yr) 15-40 > 50
Sex 2:1 > 3:1
Clinical outcome Self-limiting in most Self-limiting in most
Risk factors Pregnancy, Cirrhosis Cirrhosis, LTx, HIV
Deaths in pregnancy High (25%) Not reported
HEV superinfections Common, poor outcome Reported, poor outcome
Extra-hepatic disease Yes Yes
Chronic infection Not reported HEV-3; SOT, HIV, hem NP
Burden 3.4 million cases/yr, 70000 deaths, 3000 still births Unknown
Adopted from Khuroo et al[143] 2016. HEV: Hepatitis E virus; HIV: Human immunodeciency virus.
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with a 30-d mortality of around 34%[88,89].
Industrialized countries
Hepatitis E of indigenous origin in industrialized
regions of the World is misdiagnosed as drug induced
liver injury (DILI)[91]. This has been because of the
absence of attention to the disease by clinicians. Most
autochthonous HEV disease occurs in older individuals.
Such patients have more severe liver disease, with
higher hepatic or non-hepatic complications (15%) and
acute liver failure (8%-11%)[92]. HEV superinfection
in chronic alcoholics and alcoholic chronic liver
disease has been reported, culminating in hepatic
decompensation, progression of liver disease and
death rate approaching to 70%[89,90,93]. Autochthonous
HEV infections in industrialized countries does not
cause severe disease in pregnant women.
HEV-3 causes prolonged viremia, chronic hepa-
titis, liver fibrosis and cirrhosis in a subgroup of
immunocompromised patients. These include people
with solid organ transplant (SOT), subjects who are
human immunodeficiency virus (HIV) positive and in
those with hematological neoplasms[94,95]. Viremia up to
and beyond 3 mo suggests chronic hepatitis E. Patients
with SOT in Europe have HEV RNA prevalence of 0.9%
to 3.5%. Most of such patients are asymptomatic
or have mild liver tests abnormalities and minimal
constitutional symptoms. However, in a subgroup of
patients, chronic hepatitis E leads to rapidly progressive
liver brosis and cirrhosis over a period of 2-3 years. Of
the 85 SOT patients with HEV-3 infection, 29 patients
had self-limiting disease, 56 patients have chronic
viremia with mild liver disease and 9 patients presented
with liver fibrosis and cirrhosis. Several factors
including use of tacrolimus as an immunosuppressant,
thrombocytopenia, and low CD4 count as seen in HIV-
infected patients were listed as high risk for progression
of liver disease and development of liver fibrosis and
cirrhosis[96].
Extrahepatic manifestations
Extrahepatic manifestations known to occur with
hepatitis E include acute pancreatitis, thrombocy-
topenia, aplastic anemia, autoimmune thyroiditis,
myositis, cryoglobulinemia with skin rashes and
glomerulonephritis[97-99]. In addition, neurological
manifestations occur in 5% of HEV infections[7,100,101].
The neurological manifestations include Bell’s palsy,
encephalitis, brachial neuropathy, peripheral neuropathy
and Guillain-Barre syndrome. HEV related neurological
disease has been reported from developing and
industrialized countries and occurs in both acute and
chronic HEV infections. The long-term outcome of
neurological syndromes is variable. Pathogenesis of
extrahepatic HEV disease is not clear and might be
multifactorial. It has been proposed that immune
response to HEV may play a part in neurologic disease
namely by antiganglioside antibodies through molecular
mimicry[102]. Although HEV is a primarily hepatotrophic
virus, it has been shown to replicate in extrahepatic
sites namely kidneys, small intestine, stomach, spleen,
neurological tissues, and placenta[103,104].
MODE OF TRANSMISSION
There are several mechanisms of transmission of HEV
infection.
Waterborne transmission
Hepatitis E in poor resource countries is spread
through water contaminated by sewage[2,85]. The
way water gets contaminated is different from one
epidemic to another; however, it follows the similar
mechanism in repeat regional epidemics. Several
environmental settings contribute to contamination.
These include: (1) heavy monsoon rains; (2) floods
causing stagnation and reversal of ow in waterways
polluting drinking water sources; (3) seeping pipes
supplying drinking water laid down through or crossing
across the sewage channels; (4) overcrowding with
polluted water sources as in refugee dwellings and fast
growing slums; and (5) raw sewage owing in to open
drinking water sources (rivers, streams, unprotected
wells). It is imperative to find the mechanism of
water contamination in each epidemic so that urgent
measures can be taken to block contamination and
control the epidemic.
Person-to-person transmission
Whether HEV infections are spread from one person to
another is controversial?[105-107]. It has been proposed
that this form of transmission of HEV infection does
not occur as there are no secondary waves of hepatitis
following the epidemic[108]. However, epidemics of
hepatitis E occur due contamination of water supplies
(common source infection) and whole community
gets exposed to the virus at one time. In such a
situation secondary waves of hepatitis cases caused
by person-to-person transmission may not occur. In
contrast, epidemics of hepatitis E which lack common
source of infection are caused by person-to-person
transmission[105]. Sporadic infections are known to
spread from one person to another[106]. HEV infection
occurred in 18 (29%) of the 62 household contacts to
the 13 index cases of sporadic hepatitis E. However,
other investigators found insignificant spread from
one person to another during sporadic and epidemic
hepatitis E[109].
Zoonotic transmission
HEV prevalence in several animals in India has
been studied. In one such study, HEV infection was
ubiquitous in several animals including domestic pig,
goat, sheep and buffalo[110]. In another study, 284
domestic pigs from Maharashtra, India were studied.
122 (42.6%) and 13 (4.6%) animals were reactive for
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IgG antibodies to HEV and HEV RNA respectively[111].
All isolates from domestic pigs in India were of
genotype HEV-4. As human HEV infections, both
epidemic and sporadic in India are caused uniformly
by genotype HEV-1, it is believed that human and pig
HEV infections are unrelated and zoonotic transmission
plays an insignificant role in human infections in
India[111].
In industrialized countries, HEV-3 and HEV-4 is
spread through foodborne zoonotic transmission[112,113].
Wild boar, Sika deer and domestic pigs cross transmit
HEV, and eating parboiled esh or liver (a treat in such
countries) could be responsible for the outbreaks of
hepatitis E. A more common way of HEV spread is
through consumption of raw livers from supermarkets
or eating Corsican Figatelli sausage. Such livers and
sausages are often infected with live HEV. The waste
water of domestic pig dung in such countries may
pollute waterways and infect those who visit sea
beaches or ingest infected mollusks.
Transfusion-associated HEV
In 2004, we reported on transfusion-associated
hepatitis E from Kashmir, India[8]. In a case-control
study, we detected 13 HEV infections (IgM anti-HEV
and HEV RNA) amongst 145 multiply transfused
subjects and 2 infections amongst 250 subjects, not
transfused. In another study, three post-transfusion
HEV infections in 25 susceptible patients were detected
and traced to 4 HEV RNA positive donor samples
amongst a total of 107 samples. All the 4 donors
were asymptomatic and all transfusion-associated
infections in Kashmir were caused by genotype HEV-1.
Subsequent to this report, a Japanese patient was
found to have developed transfusion-associated HEV
infection and authors reported a complete donor-
patient sequence homology[114]. Several cases and
case series of transfusion-associated HEV infections
were reported from several countries[115,116]. In a recent
study form United Kingdom, 18 (42%) of the 42 HEV-
positive transfusion recipients had contracted HEV-3
infection. Of these, 3 had short lasting viremia, while
10 developed prolonged and persistent infection[117].
In developing countries, short lasting viremia often
occurs in healthy donors[9,118,119]. Presently, information
on HEV RNA status in potential blood donors has been
reported from many countries[79,120-122]. Viremia was
reported to occur in healthy donors in all countries and
varied from 1 out of 672 donations (Germany) to 1
out of 8416 donations (Austria). Duration of viremia
extends up to 45 d and the infectious dose of HEV is as
low as its detection by RT-PCR. Based on these data, it
was estimated that around 80000-100000 transfusion
associated HEV infections had occurred in England in
2013. Of the 7.4 million blood products administered
in Germany per year, 1600 to 5900 transfusion-
associated HEV infections had occurred. Blood or
blood products are often required for several clinical
conditions in whom hepatitis E runs a more severe
course or leads to chronic hepatitis and cirrhosis. These
include pregnancy, liver disease, SOT, HIV positive and
hematological neoplasm. In view of the above data
there is need to conduct screening of blood donors in
countries with high HEV prevalence.
Vertical transmission
HEV can be transmitted vertically to fetus and infant
from the infected mothers. We studied 8 mothers who
had HEV infection for evidence of vertical transmission.
Six babies had contracted vertically transmitted HEV
infection[18]. In another study, 26 pregnant women with
HEV infection were studied for pattern of vertically-
transmitted HEV infection[19]. Five mothers had died
prior to delivery, 2 aborted the fetuses, 4 delivered
premature babies and 15 had completed pregnancy
with normal deliveries. Out of the 19 babies evaluated,
12 were reactive for IgM anti-HEV and 10 showed
viremia. In all 15 (78.9%) had evidence of intrauterine
HEV infection. HEV infection in babies presented as
icteric hepatitis in 7, anicteric hepatitis in 5 and jaundice
alone in 3. Six newborns died with liver failure and
one due prematurity. Nine babies who survived had
short-lasting viremia and none had evidence of chronic
hepatitis or cirrhosis. Subsequent to these reports,
a number of reports have documented intrauterine
transmission of HEV infection with high maternal
and fetal mortality[87,123]. Recently HEV replication
in placenta was found to occur and correlated with
fetal and maternal mortality in acute liver failure[103].
We evaluated outcome of 36 pregnant women with
hepatitis E and the occurrence and severity of vertically
transmitted HEV infection in fetuses/neonates and
found relationship between severity of disease in fetus
with severity and outcome of disease in the mother and
postulated that acute liver failure in pregnant women
may be an example of mirror syndrome akin to acute
fatty liver of pregnancy[124].
DIAGNOSIS
Serological analysis for HEV infection has been
problematic (Table 2)[125,126]. Several issues need to
be addressed while evaluating these tests. Some
tests have problems while applying to different geno-
types. Others perform poorly in immunocompromised
persons. Cross reactions with other viral infections
have been reported. Several assays available have
been developed and evaluated by sera from patients
with recent infections. These assays often have poor
performance in sensitivity and specificity. Assays
developed and evaluated against WHO reference
reagents give more predictable results. Assays de-
veloped on either “indirect” ELISA or class capture-
ELISA technique also give better results[126]. Amongst
these, 2 assays for IgM anti-HEV marketed by the
Beijing Wantai Biological Pharmacy (Wantai Rapid
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test) and Genelabs Diagnostics, Singapore (AssureTM)
have high sensitivity and specicity. In routine clinical
practice, acute HEV infection in immunocompetent
patients can predictably be diagnosed by IgM anti-HEV.
Around 90% patients are reactive for IgM anti-HEV at
2 wk of infection and stays so for up to 5 mo[127]. In
patients with immune deficiency disease, additional
testing for HEV RNA is recommended, in view of poor
IgM response in this population.
IgG anti-HEV testing is useful in seroprevalence
studies. Rising IgG titers may help in diagnosis of
HEV infection in situations with poor IgM anti-HEV
response[128]. Testing for IgG anti-HEV titers is essential
for determining effectiveness of HEV vaccine. Antibody
titers of 2.5 WHO units/mL following vaccination or
acute HEV infection are protective.
Testing for HEV RNA is useful in several situations
which include: (1) donor screening; (2) diagnosis of
HEV infections in patients with poor IgM response; (3)
diagnosis of chronic HEV infection; and (4) evaluating
response to antiviral drug therapy[129]. In-house assays
for HEV RNA detection may have limitations and needs
to be standardized with WHO standard (genotype HEV-
3a). Conventionally HEV RNA is detected in blood and
other body fluids by RTPCR and using primers from
conserved segments of HEV. Another assay, the loop-
mediated isothermal amplification (LAMP) employs
single-tube, one-step amplication of HEV RNA. The test
is quick, reliable and needs no special equipment[130].
CONTROL AND CURE
Prevention and control of epidemics of hepatitis E
in poor resource countries is a challenging task[85].
Management should be predominantly preventing
and focusing on the supply of clean potable drinking
water, adequate sanitation and proper sewage disposal
and personal hygienic practices. During travel to
countries with high prevalence of HEV infections, one
should desist from use of contaminated drinks and
beverages and eating of uncooked shellfish. “Clean
India Campaign”, a Government of India Campaign
2014 is a USD10 billion project and is meant to clean
the environs, construct toilets in homes, societies and
schools and execute basic hygienic practices including
proper hand hygiene. It is planned that around 1.2
billion Indians shall have access to public latrines in
next 5 years[85]. Numerous endemic areas lack proper
healthcare amenities, disease surveillance means,
health education and recognizing sick patients for
referral and these activities need to be instituted[131].
Chlorination of drinking water supplies is frequently
being practiced to control epidemics and does help.
Administration of IgG from Indian source has not
succeeded in control of epidemics[106]. Availability of
hyperimmune HEV globulin and a cheap, effective and
safe HEV vaccine would help to prevent and help to
arrest the spread of the epidemics[132].
Acute hepatitis E in immunocompetent individuals
usually only need symptomatic treatment, due short
lasting viremia. Ribavirin therapy for 3 wk in patients
with severe hepatitis E causes rapid improvement
of liver enzymes and functions[133]. Despite the fact
that ribavirin is a teratogenic drug, the dangers of
untreated HEV to the mother and embryo are high,
and trials of drug therapy may be advantageous
in such patients. SOT patients should avoid eating
uncooked game meat or domestic pig meat and liver
and Figatelli sausage. In contrast, all these food items
need to be heated to inactivate the virus[38].
An algorithm for treatment of HEV-3 infection
in SOT patients has been developed (Table 3)[134].
Reduction in immunosuppression clears the virus in a
signicant proportion of patients. Calcineurin inhibitors
(cyclosporine and tacrolimus) and mTOR inhibitors
enhance HEV replication and may cause the increment
and persistence of HEV RNA[135-138]. In contrast,
mycophenolic acid (including prodrug mycophenolate
mofetil) inhibits HEV replication and may help with
HEV clearance in chronic hepatitis E. Ribavirin is the
drug of choice for patients with persistent viremia
for 3 mo[138]. PEGylated IFN can be used in patients
who have had liver transplants and not in patients
with other solid organ transplants[139]. Sofosbuvir, a
Table 2 Diagnosis of hepatitis E virus infection
Test Method Uses Comments
IgM anti-HEV ELISA Acute infection Assays vary in performance, issue of genotype applicability, poor performance in
immune disorders, cross-reactive with other viral infections
ICT (POCT)
IgG anti-HEV ELISA Seroprevalence Assays vary in performance
ICT (POCT) Acute infection
Natural protection
Vaccine efcacy
HEV RNA NAT Acute infection Viremia short-lasting, in-house assays vary in performance, advantage immune disorders
Conrm chronicity
Anti-viral response
Donor screening
HEV antigen EIA Acute infection 81% concordance with HEV RNA
Adopted from Khuroo et al[143], 2016. HEV: Hepatitis E virus; ICT: Immunochromatographic test; POCT: Point of care test; NAT: Nucleic acid test; EIA:
Enzyme immunoassay.
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nucleotide analog inhibitor of hepatitis C infection
polymerase, additionally hinders HEV replication
in vitro by inhibiting the viral RNA-dependent RNA
polymerase[140]. The role of Sofosbuvir in acute and
prolonged HEV infection needs closer examination.
Some patients may develop liver brosis, cirrhosis and
liver failure and are candidates for liver transplantation.
HEV VACCINE
HEV-239 is made of VLP, expressed in E. coli (368-606
aa of ORF2) from HEV-1 Chinese strain and has 2
epitopes (533 to 552 aa) and incites an incredible T
cell-dependent antibody response[12,141]. The vaccine
has effectively completed trials in China and is
marketed (Hecolin) in 30-lg doses for 3 dose regimen
(0, 1 and 6-mo). At 4.5 years, vaccine offers efcacy
was 86.8%. The vaccinated patients have protective
antibody levels in 87% as against 9% in the control
group[142]. The vaccine has been shown to give cross-
protective efficacy between genotype HEV-1 (the
vaccine product) to HEV-4 (infection prevalent in area
of study).
For the global launch of HEV-239 vaccine, we need
safety data in children, elderly patients, patients with
chronic liver disease, SOT, HIV and those with immune
disorders[143]. Data regarding safety of HEV-239 in
pregnant women needs to be extended. Vaccine safety
when used concomitantly with other vaccine needs
consideration. Post-marketing and cost-effectively
studies can be conducted once a vaccine is available
in other countries. HEV-239 has been found highly
effective in population where HEV-4 is prevalent
with low endemicity at HEV attack rate of 0.03%. It
is important to determine efficacy of vaccine in the
Indian subcontinent where HEV-1 infection is prevalent
with very high endemicity at an attack rate of 7.36%.
Also vaccine efcacy studies in regions where genotype
HEV-3 is prevalent need to be done[132].
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Table 3 Effect of drugs on hepatitis E virus replication and their use and impact on immunosuppressant therapy during chronic
hepatitis E virus infection in solid organ transplant patients
Class Drug Effect on HEV replication Clinical use
Calcineurin inhibitors Cyclosporine, tacrolimus Stimulates HEV replication with increase in HEV load and
promotes HEV persistence
Reduce dose
mTOR inhibitors Rapamycin, everolimus Stimulates HEV replication with increase in HEV load Reduce dose
Antimetabolite
immunosuppressant
Mycophenolate mofetil Inhibits HEV replication and helps HEV clearance Continue the drug
Guanosine analog Ribavirin Inhibits HEV replication and causes HEV clearance Primary drug for therapy
Cytokines Pegylated interferon αInhibits HEV replication and causes HEV clearance Indicated if Ribavirin therapy fails
Nucleotide analog Sofosbuvir Inhibits HEV replication in vitro Unclear, clinical trials indicated
HEV: Hepatitis E virus.
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P- Reviewer: Chuang WL, Gallegos-Orozco JF, Kaplan DE
S- Editor: Ma YJ L- Editor: A E- Editor: Wang CH
Khuroo MS
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